The goal of this K08 is to provide Dr. H. Henry Lai with an intense mentored basic research experience to bridge a successful transition from supervised research to a career as an independent investigator. Dr. Lai is an exceptionally qualified candidate. His long-term career goal is to become a successful urologist- scientist, innovating at the interface between the laboratory and the clinic, to address critical research areas in neurourology and bladder/voiding disorders. His background and training demonstrated unequivocally his potential and commitment to scientific research. Dr. Lai has engaged in bench research and has been productive in publishing basic science papers (six first-authored papers). Even though his solid background in bladder physiology and pharmacology has laid the foundation of success, as Dr. Lai continues to develop his independent program, he realized that his previous exposure to behavioral pain research and molecular neuroscience is inadequate, and he would need additional protected research time in the lab to succeed. Dr. Lai has proposed a comprehensive career development plan that is specifically tailored to his individual needs. This plan is anchored on his existing and productive collaboration with his Mentor, Dr. Robert Gereau, Ph.D. Dr. Gereau is an internationally renowned authority in molecular and behavioral pain research. He has independent NIH funding in bladder pain research and CNS pain sensitization, and has mentored many trainees to become independent and productive. His devotion and skill in mentoring won him the highest honor at Washington University. Together, Drs. Lai and Gereau have generated strong preliminary data here and have published together. There are many strengths of Dr. Lai's career development plan, including easy accessibility to the Mentor with frequent one-on-one interaction, a focused and structured didactic program, utilization of the vast CTSA resources at Washington University, a devoted team of Career Advisors who are all successful clinician-scientists, and a plan with well defined objectives, milestones, and monitoring mechanisms. The institutional environment for career development at Washington University and in the Division of Urology is outstanding. Dr. Andriole (Chief of Urology) and Dr. Eberlein (Chairman of Surgery) have pledged their full department commitment to provide Dr. Lai with 60% protected research time. Dr. Lai already has an existing laboratory space, equipments, start-up funds, and personnel to facilitate his research. The role of metabotropic glutamate receptor 5 (mGluR5) in bladder pain Research Proposal: Dr. Gereau (Mentor) has previously shown that activation of metabotropic glutamate receptor subtype 5 (mGluR5) and its downstream signaling targets, ERK1/2 (extracellular signal-regulated kinases), in spinal cord dorsal horn increases the excitability of the spinal neurons and contributes to the development of somatic pain hypersensitivity and spinal central sensitization. While the roles of spinal mGluR5 have been studied in somatic pain models, its role in the development of bladder pain hypersensitivity is poorly understood. The objective of this proposal is to investigate the roles of spinal mGluR5 and its signaling targets ERK1/2 in the development of central sensitization in mouse models of bladder pain. Our preliminary data show that in a mouse model of bladder pain, development of bladder hyperalgesia is associated with robust spinal cord ERK1/2 activation (phosphorylation). Functional blockade of spinal ERK1/2 activation attenuates the distention-evoked bladder nociception. Activation of spinal mGluR5 also sensitizes the naive bladder to distention. Systemic inhibition of mGluR5 attenuates the bladder nociception induced by noxious distention and inflammation. Together, preliminary results indicate that mGluR5 and ERK1/2 activation for critical for full expression of bladder pain hypersensitivity. We hypothesize that activation of spinal mGluR5 induces downstream activation of spinal ERK1/2 signaling, and contributes to spinal central sensitization and the development of bladder hyperalgesia in mouse models of bladder pain. The following specific aims will be addressed using a combination of pharmacologic and genetic approaches: Aim 1: To test the hypothesis that spinal mGluR5 modulates bladder hyperalgesia in mouse models of bladder pain (cyclophosphamide cystitis, bacterial cystitis). Aim 2: To test the hypothesis that mGluR5 modulates bladder hyperalgesia via spinal ERK1/2 signaling and by modulating spinal neuronal excitability. The study of bladder pain has clinical significance in relation to a number of urologic conditions such as interstitial cystitis and bladder infection. Ths proposal addresses a major gap in bladder pain research by investigating the molecular pathways that underlie CNS pain sensitization. The research is innovative because bladder pain hypersensitivity will be investigated from an entirely new perspective at the level of the CNS with multidisciplinary collaboration. The approach also provides an optimal training platform for Dr. Lai to learn new expertise in molecular/behavioral pain research and neuroscience to become an independent researcher.